An Updated Economic Assessment of Moxidectin Treatment Strategies for Onchocerciasis Elimination

Abstract Background Concerns that annual mass administration of ivermectin, the predominant strategy for onchocerciasis control and elimination, may not lead to elimination of parasite transmission (EoT) in all endemic areas have increased interest in alternative treatment strategies. One such strategy is moxidectin. We performed an updated economic assessment of moxidectin- relative to ivermectin-based strategies. Methods We investigated annual and biannual community-directed treatment with ivermectin (aCDTI, bCDTI) and moxidectin (aCDTM, bCDTM) with minimal or enhanced coverage (65% or 80% of total population taking the drug, respectively) in intervention-naive areas with 30%, 50%, or 70% microfilarial baseline prevalence (representative of hypo-, meso-, and hyperendemic areas). We compared programmatic delivery costs for the number of treatments achieving 90% probability of EoT (EoT90), calculated with the individual-based stochastic transmission model EPIONCHO-IBM. We used the costs for 40 years of program delivery when EoT90 was not reached earlier. The delivery costs do not include drug costs. Results aCDTM and bCDTM achieved EoT90 with lower programmatic delivery costs than aCDTI with 1 exception: aCDTM with minimal coverage did not achieve EoT90 in hyperendemic areas within 40 years. With minimal coverage, bCDTI delivery costs as much or more than aCDTM and bCDTM. With enhanced coverage, programmatic delivery costs for aCDTM and bCDTM were lower than for aCDTI and bCDTI. Conclusions Moxidectin-based strategies could accelerate progress toward EoT and reduce programmatic delivery costs compared with ivermectin-based strategies. The costs of moxidectin to national programs are needed to quantify whether delivery cost reductions will translate into overall program cost reduction.


Text S1. Calculation of elimination probabilities and EoT90
The stochastic EPIONCHO-IBM onchocerciasis transmission model [1] was used by Kura et al. [2] to project the number of treatment rounds necessary to achieve of elimination of transmission (EoT) of Onchocerca volvulus for a range of strategies and epidemiological scenarios (see Table 1 of Main Text) in endemic (closed) populations of size 440 individuals.Given the stochastic nature of infection events in a model such as EPIONCHO-IBM (with demographic and transmission stochasticity), it is possible for microfilarial prevalence values to fluctuate after cessation of treatment even after the transmission breakpoint has been crossed.Therefore, EoT was considered to have been achieved within a model run when skin microfilarial prevalence was 0%, 50 years after the last MDA treatment round.As the model is stochastic, the number of rounds needed to achieve EOT will vary across different model runs, and the probability of elimination is thus calculated as the proportion of (in 500) runs that achieve EOT as defined above.The probabilities of elimination were calculated after every two years of treatment and plotted against the number of years of mass drug administration (MDA) with ivermectin or moxidectin.For the analysis presented in the Main Text, the number of rounds reported for each scenario was based on the number needed to reach a 90% probability of elimination (EoT90) over such 500 model runs.A detailed description of the methodology for the simulations conducted to investigate the epidemiological impact of moxidectin in comparison to ivermectin MDA can be found in Kura et al. [2].

Text S2. Drug effects
The drug effects of ivermectin had been parameterised by fitting appropriate functions of time following treatment to data obtained from a previous systematic review and meta-analysis of single-dose ivermectin trials (Figure S1A) [3].
Moxidectin was assumed to exert the same types of effects on the parasite as ivermectin, and these effects were parameterised by fitting the same functions as used in Basáñez et al. [3] to the Phase II moxidectin trial data [4] (Figure S1B).As reflected in the error bars presented in Figure S1, there is a greater amount of interindividual variation in treatment responses to single-dose ivermectin than to singledose moxidectin (see also Opoku et al. [5]).However, due to the fact that it is still unknown whether the patterns of inter-individual variation observed in the Phase II and III clinical trials will apply to consecutive treatment rounds, the consequences of such variation in the microfilaricidal and/or embryostatic drug effects was not considered within this study (but see [6]).
The model also incorporates a permanent sterilizing effect of female worms.In the previous modelling study and economic analysis of moxidectin, this effect was referred to as an anti-macrofilarial action of treatment [7].This action assumes, following Plaisier et al. [8], that repeated exposure of adult worms to treatment permanently reduces their rate of microfilarial production.This reduction was assumed to be 35% per standard (150 µg/kg) dose of ivermectin [8].As no data yet exist on the effect of multiple doses of (8 mg) moxidectin, we assumed the same magnitude of permanent sterilizing effect as for ivermectin.Given that moxidectin has a longer half-life [9,10], and more prolonged effect on microfilaridermia after a single dose [4,5,11], it is plausible to hypothesize that the permanent sterilizing effect of moxidectin may be greater than that of ivermectin.Although currently there are no data with which to scrutinise this conjecture, we investigated the repercussions of varying the magnitude of the putative permanent sterilizing effect between the two drugs.We considered a scenario in which ivermectin had half the permanent sterilizing effect compared to moxidectin (with ivermectin causing an irreversible reduction in microfilarial production of 17.5% per treatment dose/round, and moxidectin causing 35% reduction per dose/round).Table S1 presents the parameter estimations for the drug effects of ivermectin and moxidectin.Given the uncertainty surrounding the magnitude of this irreversible sterilizing drug effect, the previous economic evaluation of moxidectin conducted by Turner et al. [7] investigated a range of values, from 1% to 30%, with a nominal value of 7% cumulative reduction of microfilarial production, per treatment dose/round, for both ivermectin and moxidectin (see Text S3: Comparison with the previous economic analysis).[4].The temporal dynamics of a single standard dose of ivermectin, previously parameterized by fitting to microfilarial load data collated as part of a systematic review and modelling meta-analysis [3], is shown as the solid red line in (A) by way of validation (i.e., not fitted to the Phase II trial data).The temporal dynamics of a single dose of moxidectin was fitted to the trial data on microfilarial loads from treated participants, and drug effect parameters were estimated [7] using the same approach described in [3], shown as the solid blue line in (B).Error bars are the 95% confidence intervals (95% CIs) around the data at each time-point following treatment.As the variance of microfilarial load for moxidectin is substantially smaller than for ivermectin, the 95% CIs for the moxidectin data points are narrower and may not be visible.S6A and Table S7A) Moxidectin: 0.345 (assumed to be equal to ivermectin's) as estimated in [8] Modelling for policy: PRIME-NTD For the analyses presented, we adhered to the Five Principles of the Neglected Tropical Disease (NTD) Modelling Consortium for good practice in policy-relevant NTD modelling [12].Table S2 briefly describes the five tenets, how they were fulfilled, and where in the Main Text and/or Supplementary Material they can be found.(B) Enhanced coverage scenario: 80% therapeutic coverage of total population and 1% systematic nonadherence.
It was assumed that both drugs exert a cumulative, permanent reduction of the rate of microfilarial production by adult female worms of 35% per treatment round with a standard dose of ivermectin (150 µg/kg) or moxidectin (8 mg).
For biannual treatment strategies, results are based on rounding up to whole numbers regarding the number of years of treatment needed to achieve 90% probability of reaching elimination of transmission (EoT90).
* EoT90 not attained within the 40-year time horizon.

Figure S1 .
Figure S1.The dynamic effect of a single dose of ivermectin (A) and moxidectin (B) onskin microfilarial load.The data points represent the proportion (in percent) relative to pre-treatment of skin microfilarial loads (the mean of four microfilarial counts/mg, from four (weighed) skin snips per individual participant) collected at 1, 2, 3, 6, 12 and 18 months after treatment from (A) the 45 control participants who took a single standard dose, 150 µg/kg of ivermectin) and (B) the 38 treated participants who took a single dose, 8mg of moxidectin) as part of the Phase II clinical trial of moxidectin for the treatment of onchocerciasis[4].The temporal dynamics of a single standard dose of ivermectin, previously parameterized by fitting to microfilarial load data collated as part of a systematic review and modelling meta-analysis[3], is shown as the solid red line in (A) by way of validation (i.e., not fitted to the Phase II trial data).The temporal dynamics of a single dose of moxidectin was fitted to the trial data on microfilarial loads from treated participants, and drug effect parameters were estimated[7] using the same approach described in[3], shown as the solid blue line in (B).Error bars are the 95% confidence intervals (95% CIs) around the data at each time-point following treatment.As the variance of microfilarial load for moxidectin is substantially smaller than for ivermectin, the 95% CIs for the moxidectin data points are narrower and may not be visible.

Figure S2 .
Figure S2.Projected number of years to achieve 90% probability of elimination of transmission (EoT90) for three endemicity levels (baseline microfilarial prevalence) under two assumptions regarding the magnitude of the permanent sterilizing effect on O. volvulus of ivermectin and moxidectin assuming minimal coverage.(A) A dose (150 µg/kg) of ivermectin irreversibly reduces microfilarial productivity of female worms by 17.5%, whereas a dose (8mg) of moxidectin exerts a reduction of 35%, per treatment round.(B) Both ivermectin and moxidectin exert a permanent sterilizing effect of 35% per treatment round.* Elimination not attained within the 40-year time horizon.Minimal coverage: 65% therapeutic coverage of total population and 5% systematic non-adherence.

Table S3 .
Projected number of treatments per 100,000 individuals needed to achieve EoT90 or reach the 40-year time horizon without achieving EoT90 for the endemicity levels, treatment strategies and coverage scenarios investigated (A) Minimal coverage scenario: 65% therapeutic coverage of total population and 5% systematic non-adherence.

Table S4 .
Total (absolute) programmatic delivery cost (in US$) for the different endemicity levels, treatment strategies and coverage scenarios investigated assuming that the total yearly cost would increase by 60% when treating biannually

Table S5 .
Total (absolute) programmatic delivery cost (in US$) for the different endemicity levels, treatment strategies and coverage scenarios investigated assuming that the total yearly cost would increase by 100% when treating biannually Enhanced coverage scenario: 80% therapeutic coverage of total population and 1% systematic non-adherence.The values represent the projected total programmatic delivery cost of the different treatment strategies over a 40-year time horizon and exclude the economic value of the drugs.The annual economic cost of the aCDTI strategy was assumed to be US$50,535 per 100,000 individuals.It was assumed that both drugs exert a cumulative, permanent reduction of the rate of microfilarial production by adult female worms of 35% per treatment round with a standard dose of ivermectin (150 µg/kg) or moxidectin (8 mg).Values highlighted in green shading indicate scenarios where 90% probability of achieving EoT (EoT90) was attained within 40 years of treatment; values highlighted in pink shading indicate those scenarios for which EoT90 was not achieved within 40 years.

Table S6 .
Projected number of years to achieve 90% probability of elimination of transmission (EoT90) and relative programmatic delivery cost of the different treatment strategies compared to aCDTI over the 40-year time-horizon, under minimal coverage scenario, when varying the magnitude of the permanent sterilizing effect onThe values in brackets represent the projected relative proportions (in percent) of total programmatic delivery cost of the different treatment strategies compared to aCDTI over a 40year time horizon and exclude the economic value of the drugs.Values of 0% signify that the costs are the same as aCDTI; those accompanied by a minus sign indicate a relative reduction in cost; those accompanied by a plus sign indicate a relative increase in cost.
*As EoT was not attained with aCDTI within the 40-year time horizon, the relative costs are calculated based on costs of 40 years of aCDTI.The corresponding projections of the total programmatic delivery costs are presented in TableS7.

Table S7 .
Total (absolute) programmatic delivery cost (in US$) for the different endemicity levels and treatment strategies, under minimal coverage scenarios when varying the magnitude of the permanent sterilizing effect on O. volvulus adult female worms and assuming that biannual delivery increases the yearly cost of treatment by 60% (A) Ivermectin has half the magnitude of the permanent sterilizing effect compared to moxidectin Ivermectin and moxidectin have the same magnitude of the permanent sterilizing effectThe values represent the projected total programmatic delivery cost of the different treatment strategies over a 40-year time horizon and exclude the economic value of the drugs.(A) The cumulative, permanent reduction in microfilarial production is 17.5% per treatment round for ivermectin and 35% per round for moxidectin.(B) The cumulative, permanent reduction in microfilarial production is 35% per treatment round for both drugs.Minimal coverage scenario: 65% therapeutic coverage of total population and 5% systematic onadherence.Values highlighted in green shading indicate scenarios where 90% probability of achieving EoT (EoT90) was attained within 40 years of treatment; values highlighted in pink shading indicate those scenarios for which EoT90 was not achieved within 40 years.